Multiple Sclerosis
Multiple sclerosis (MS) is a neurodegenerative disease characterized by the destruction of myelin cells within the central nervous system. MS is a heterogeneous disease, having various pathologies, and potentially, etiologies. There are no symptoms that are unique to MS, complicating the ability of individuals to receive accurate diagnoses. Optic neuritis, internuclear ophthalmoplegia and fatigue are more frequently indicative of MS over other neurological disorders, as is relapses and remissions of symptoms. (1) The prevalence rate of MS is 1 in 700, or 0.14% in the U.S., and is approximately 2.4 times more common in women than men. The median age of onset is 23.5 years old, with women diagnosed and average of 5 years earlier than men. Treatments for MS usually focus on the mitigation of symptoms, as currently there is no cure. (http://www.msfacts.org) There is strong evidence for an autoimmune component to MS. (1,2) Identified genetic risk factors An increased risk of multiple sclerosis is associated with certain alleles of major histocompatibility complex (MHC) genes, especially the HLA-DRB1 locus, as well as a cumulative effect produced by mutations in several non-MHC genes, including IL-7R. Evidence suggests that IL-7R polymorphisms may be associated with an increased risk of MS. (3) People of Northern European decent experience the highest rates of MS, while those of African, Asian or American Indian decent have the lowest. (4) Environmental risk factors Multiple studies, including an analysis of the Nurses' Health Study have pointed to a potential protective effect against MS from exposure to sunlight, either as a direct result of increased UV exposure, or from the resulting elevated levels of vitamin D. (5) Similarly, geographical locations – particularly latitude – have been indicated as a factor in assessing MS risk. (6) Smoking is associated with an increased risk of MS diagnosis and disease progression. (7) Basis for 23andMe evaluation 23andMe characterizes an individual’s relative lifetime risk of having multiple sclerosis based on the following factors: ethnicity; and the status of two single nucleotide polymorphisms (SNP) -- rs3135388 in the HLA-DRB1 gene, and rs6897932 in the IL-7RA gene. The IL7Ra protein is required for signaling by two growth factors, IL-7 and TSLP, which play an important role in immune cell differentiation and maintenance. IL7Ra exists either in the membrane-bound form, or as a free-floating protein that can be released into the bloodstream. The ratio of these two forms of the protein appears to affect immune cell activity. Individuals with the C form of the rs6897932 SNP have an increased amount of free-floating ILRa, potentially leading to a heightened level of immune cell activity, or conversely, inhibiting the cells’ ability to successfully clear infections. Given the evidence for an immunological component to MS, either of these proposed mechanisms appears plausible. The DRB1 gene encodes a protein that makes up part of the HLA complex. Together, this complex of proteins provides the immune system with the ability to recognize the myriad foreign agents it is exposed to, and to ultimately react to them appropriately. Individuals of European decent with a particular variant of the HLA-DRB1 gene, termed 1501, have been confirmed to have an increased risk of having MS, although a specific mechanism for BRB1's involvement in this process has not been identified. (https://www.23andme.com) 23andMe results: Potential value and limitations John Burke's personal genomic report indicates that he has a 0.5x relative risk of developing MS between the ages of 0 and 79, compared to other men of European decent. Dr. Burke was found to not have either of the SNPs associated with an increased risk of developing MS. Multiple sclerosis is not clearly defined by one set of symptoms or features, nor does the cause of the disease appear to be consistent across individuals with the disease. Some evidence suggests that an underlying genetic state predisposes individuals to MS, though studies conducted on the rates of MS in identical twins indicate that the relative genetic contribution to this disease is low compared to environmental causes. (3,8) For a rare disease like MS, relative risk may vary greatly among a population. Although a relative risk swing of 0.5 to 2 may appear to demonstrate a valuable indicator for the likelihood of disease, the absolute risk of disease for any individual remains very low. This is especially important to remember in the context of a disease like MS, in which environmental factors appear to trump genetics. Furthermore, the magnitudes in which the genes focused on by 23andMe – and more specifically, the particular SNPS – actually play a part in the MS disease process remain unclear. (9) Even given a significant role for these two genes in MS, the clinical value of the findings reported by 23andMe remains contentious (see excerpt from MD’s perspective). In general, one needs to be cautious when interpreting their personalized results from 23andMe (or a similar service) and it appears in particular, the results pertaining to multiple sclerosis. References 1. Weiner HL (2004) Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Archives of neurology 61(10):1613-1615. 2. Roach ES (2004) Is multiple sclerosis an autoimmune disorder? Archives of neurology 61(10):1615-1616. 3. International Multiple Sclerosis Genetics C, et al. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. The New England journal of medicine 357(9):851-862. 4. Kantarci O & Wingerchuk D (2006) Epidemiology and natural history of multiple sclerosis: new insights. Current opinion in neurology 19(3):248-254. 5. van der Mei IA, et al. (2003) Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. Bmj 327(7410):316. 6. Alonso A & Hernan MA (2008) Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 71(2):129-135. 7. Franklin GM & Nelson L (2003) Environmental risk factors in multiple sclerosis: causes, triggers, and patient autonomy. Neurology 61(8):1032-1034. 8. Sadovnick AD, et al. (1993) A population-based study of multiple sclerosis in twins: update. Annals of neurology 33(3):281-285. 9. Nielsen NM, et al. (2005) Familial risk of multiple sclerosis: a nationwide cohort study. American journal of epidemiology 162(8):774-778.